The Future of Immunotherapy in Prostate Cancer

The article reviewed

Dr. Susan Slovin, an expert on immunologic treatments for genitourinary malignancies, has crafted a well-written and comprehensive review of the state of the art in immunotherapy for prostate cancer. Her article highlights the differences between passive and active immunotherapy, discusses difficulties in monitoring an antitumor immune response, and reviews ongoing and completed clinical trials of both passive and active immunotherapy. While Dr. Slovin's article strikes an enviable balance between comprehensiveness and brevity, a small number of areas might prove worthy of further elaboration.

Immunotherapy With Monoclonal Antibodies

Dr. Slovin carefully reviews the development of a monoclonal antibody to prostate-specific membrane antigen (PSMA). This antibody was originally developed by the Bander group and evaluated in an unconjugated form (J591).[1] Subsequently, evaluation has progressed through several robust phase II trials, including a number involving radiolabeled constructs (yttrium-90 and lutetium-177). While impressive targeting results have been obtained with J591-based monoclonal antibodies, the rate of objective clinical responses in patients with advanced disease has been somewhat underwhelming to date.[2]

While moving to earlier disease stages is a logical extension of these studies, another potential approach to improve clinical efficacy might be to combine antibody-mediated targeting with active vaccination. Such an approach has shown synergistic efficacy in laboratory studies by the Reilly group,[3] and is currently being extended to the breast cancer arena in an important phase II study initiated by Dr. Leisha Emens.[4] Although dauntingly complex from a regulatory perspective, combinatorial studies using anti-PSMA monoclonal antibodies in combination with one of the active immunotherapy approaches for prostate cancer in the later stages of clinical development such as sipuleucel-T (Provenge) or GVAX might be considered in the near future.

It is also notable that a small number of additional targeted monoclonal antibodies are in early stages of development for prostate cancer. These agents include a fully human monoclonal antibody directed against prostate stem cell antigen (PSCA), being codeveloped by Merck and Agensys, Inc. Since PSCA appears to be relatively overexpressed on prostate metastases,[5] PSCA might prove a particularly attractive target in men with advanced disease.

Another target currently under consideration in the clinic is the pro-inflammatory cytokine interleukin (IL)-6. Preclinical data show that IL-6 promotes the survival and proliferation of prostate cancer cells, and serum IL-6 levels are a marker for poor prognosis in men with advanced disease. The current clinical trial of this agent employs a combinatorial approach, administering mitoxantrone-based chemotherapy along with a chimeric monoclonal antibody developed by Centocor, Inc. An interesting facet of this trial is that the combinatorial approach is being explored early on, perhaps suggesting a wider acceptance of the notion that combination approaches will prove necessary to achieve clinical efficacy with immunotherapy.

Immune Checkpoint Blockade

Dr. Slovin provides an eloquent rationale for approaches combining immune checkpoint blockade with active immunotherapy in prostate cancer, and discusses an ongoing trial in which GVAX immunotherapy is combined with anti-CTLA-4 (ipilimumab) in men with hormone-refractory prostate cancer. It is perhaps notable that a similar combinatorial approach combining anti-CTLA-4 with a viral-based anti-PSA vaccine is currently enrolling patients at the National Cancer Institute. The principal investigator of this trial, Dr. James Gulley, and his colleague Dr. Philip Arlen have conducted a number of combinatorial trials with this vaccine vector, including combination with radiotherapy[6] and antiandrogen administration.[7]

While CTLA-4 blockade is currently the cornerstone of most of the ongoing combinatorial immunotherapy approaches, it is noteworthy that CTLA-4 knockout mice have a fairly significant phenotype, developing multisystem autoimmunity that proves fatal at 18 to 28 days of age[8]. These data suggest that effective blockade of the CTLA-4/B7-1/2 axis might be associated with a measurable incidence of autoimmunity in the clinic; in fact, this has been observed.[9] Thus, a number of additional checkpoints are under study in multiple laboratories, with the eventual goal of translation to combinatorial or single-agent studies in men with prostate cancer.